Positron Emission Tomography (PET) permits the non-invasive quantification of regional myocardial blood flow, substrate fluxes and biochemical reaction rates in mumol or ml/min/g. PET's uniqueness derives from a quantitative imaging capability, the availability of numerous physiologic tracers and the in vivo application of tracer kinetic principles. Measurements of true tracer tissue concentrations and their time dependent changes, fundamental for estimating rates of processes, are possible with high temporal PET imaging but are limited by partial volume effect, activity spillover and data noise. Current PET scanners visualize simultaneously the entire left ventricle and, thus, permit two-dimensional mapping of the geographic distribution of functional processes. Moreover, myocardial oxidative metabolism can be estimated with C-11 acetate while preliminary studies have suggested the possibility of non-invasive measurements of myocardial rates of protein synthesis. Lastly, PET has provided novel information on metabolic alterations in ischemic and post- ischemic myocardium which, however, remain mostly phenomenological. The proposed research will investigate solutions to technical limitations for more accurate measurements of regional tracer concentrations in myocardium and arterial blood. It will develop tools for mapping quantitatively the three-dimensional distribution of functional processes in the LV myocardium, to quantify extent and severity of abnormal processes, and for evaluating contractile function from gated PET images. A second goal is to biochemically validate and test in vivo a tracer kinetic model for simultaneous measurements of regional myocardial blood flow, oxygen consumption and oxygen extraction by a single C-11 acetate injection, and, to explore and biochemically validate a tracer kinetic approach with radiolabeled leucine for the non-invasive measurement of regional myocardial protein synthesis rates. Lastly, studies will be performed to provide more mechanistic explanations for previously made observations in ischemic and post-ischemic myocardium in experimental animals and in humans. The studies will also include the development of an animal model of "myocardial hibernation" which will then be metabolically characterized. The proposed research will largely be performed in experimental animals, including biochemical assays for myocardial tissue and blood. After validation of the newly developed approaches in animals, their feasibility will be tested in humans. The proposed research is anticipated to improve the accuracy of non-invasive tools for estimating functional processes in human myocardium as well as to provide new means for probing the humans heart's physiology and pathophysiology.